How are the huge number of different neuronal cell types that make up our brain specified, and how do neuronal activity and other environmental stimuli modify their cell state? My lab investigates the gene regulatory mechanisms that generate diverse neuronal cell types and that modify gene expression in response to stimuli.

A major focus of my lab is the role of genome folding and chromatin structure in controlling neuronal gene expression. DNA is a 3D molecule that gets packaged and folded inside the nucleus of living cells. If it were to be fully extended, the DNA that makes up a single diploid human genome would be over two meters long, yet our cells fold and package this DNA so that it fits in a micron-scale nucleus. This folding is not random. Instead, DNA is organized into a hierarchy of structures that serve diverse functions, such as spatially separating the active and inactive regions of the genome and delimiting the sets of genes that are controlled by noncoding regulatory elements. At finer size scales, DNA associates with proteins to form chromatin. The structure and composition of chromatin surrounding a given gene controls whether and to what extent that gene will be transcribed into RNA. All these processes together instruct different cells to express different genes at different levels, which allows a single genome to generate the huge number of distinct cell types that make up our bodies.

We primarily use the mouse olfactory system to study how the 3D folding of the genome defines neuronal identity. The mouse olfactory system detects the volatile odorant compounds present everywhere in the world around us by deploying a huge number of odorant receptor (OR) proteins. Each sensory neurons expresses only a single OR gene, and this choice of a single OR defines its neuronal subtype and controls its function. This cell fate decision is controlled by a dramatic remodeling of the genome in these cells, which allows specialized regulatory DNA elements to activate the chosen OR gene. Ongoing work in the lab is investigating the molecular mechanisms that control genome folding and chromatin state over the process of neuronal differentiation. Additional projects in the lab are examining how the packaging of DNA into chromatin and the folding of chromatin into 3D structures gets modified by neuronal activity and other signals.

To accomplish these goals, we have pioneered the application of molecular and genomic methods for monitoring DNA packaging and genome folding to primary neurons isolated from mice. My lab combines these approaches with genetic strategies for manipulating gene function in vivo, which allows us to interrogate the molecular mechanisms that control genome folding in living animals.